Enter RGS2, or regulator of G-protein signaling 2, a protein that has fascinated cardiovascular physiologists for more than two decades. RGS2 acts as a negative regulator of Gq-coupled receptors, and chief among its targets is the angiotensin II type 1 receptor, or AT1R, the receptor through which angiotensin II executes many of its pressor and remodeling effects. Mice engineered to lack RGS2 throughout the body develop severe hypertension and prolonged vasoconstrictor signaling, and reduced RGS2 expression has been documented in hypertensive patients, where it correlates with exaggerated calcium mobilization and ERK1/2 phosphorylation in response to angiotensin II. RGS2 is also abundantly expressed in myeloid cells, which raises an intriguing paradox: if immune cells promote hypertension and RGS2 restrains angiotensin II signaling, should removing RGS2 specifically from myeloid cells unleash worsened hypertensive disease?

A team led by Nakagawa and colleagues set out to answer precisely that question. Using an elegant conditional knockout strategy, they generated mice in which RGS2 was selectively ablated in myeloid cells, a model designated RGS2 LysM-KO, and then challenged these animals with chronic angiotensin II infusion. The expectation, shared by the investigators themselves and by much of the field, was that loss of the AT1R brake in macrophages and related cells would amplify inflammatory signaling and thereby exacerbate hypertension and cardiovascular-renal injury.

The results defied those expectations. Across every measure the researchers examined, the myeloid-specific RGS2 knockout mice behaved essentially like their normal counterparts. Blood pressure responses to chronic angiotensin II were indistinguishable between the groups. Cardiac and renal damage, typically hallmarks of sustained pressor challenge, did not differ. Vascular dysfunction was unchanged, and inflammatory profiles failed to reveal any meaningful divergence attributable to the loss of myeloid RGS2. The authors concluded that myeloid RGS2 is not involved in angiotensin II-induced hypertension or cardiovascular-renal organ damage, a finding with significant conceptual implications.

Perhaps the most important implication is what the study says about the devastating hypertension of whole-body RGS2 deficiency. If deleting the protein in immune cells accomplishes nothing, then the severe, damaging hypertension seen when RGS2 is absent everywhere must be driven exclusively by altered RGS2 signaling in vascular and renal epithelial tissues rather than by the immune system. The brake that matters, in other words, is the one applied within the blood vessel wall and the kidney tubule, not the one applied inside infiltrating macrophages. This reallocation of responsibility helps sharpen where therapeutic efforts to modulate RGS2 signaling should be aimed.

Writing in a linked commentary in the same journal, Lorenzo A. Calò, Martina Cacciapuoti, and Paul A. Davis place these murine findings in a striking human context. Their laboratory has long studied Gitelman’s and Bartter’s syndromes, rare genetic tubulopathies caused by defects in specific kidney transporters and ion channels. These disorders are, in a sense, the mirror image of hypertension: they represent human models of endogenous angiotensin II signaling antagonism. Patients with Gitelman’s or Bartter’s syndrome display marked activation of the renin-angiotensin-aldosterone system, with high circulating levels of both angiotensin II and aldosterone, yet despite this hormonal surge they present with hypotension or normotension rather than hypertension.

The clinical paradox deepens on closer inspection. Beyond their low blood pressure, patients with these syndromes show hyporesponsiveness to pressor agents and display activation of antiatherosclerotic and antiremodeling defenses. Their vascular biology features reduced Rho kinase signaling, increased nitric oxide bioavailability, and diminished oxidative stress and oxidative stress-related signaling, all in the face of elevated angiotensin II. Something powerful is damping down the signaling that angiotensin II normally delivers through the AT1 receptor, and the commentary authors argue that RGS2 is a central player in this endogenous antagonism.

The cellular evidence they have accumulated is compelling. In fibroblasts derived from patients with Gitelman’s and Bartter’s syndromes, both RGS2 RNA and protein abundance are increased compared with cells from healthy normotensive subjects. Functionally, this elevated RGS2 blunts angiotensin II signaling at multiple levels: it attenuates short-term signaling, including intracellular calcium release and the calcium-protein kinase C pathway in vascular smooth muscle cells, and it also dampens long-term proliferative and profibrotic responses that drive remodeling. Most tellingly, when the researchers silenced RGS2 in fibroblasts from these patients, the cells reverted to a hypertensive-like angiotensin II response, characterized by increased intracellular calcium release and ERK1/2 phosphorylation. In other words, removing the RGS2 brake in human cells restores the very signaling signature that defines hypertensive disease.

Taken together, the mouse knockout study and the human syndrome data demonstrate that RGS2 regulation of angiotensin II signaling through the Gq/AT1R axis, and its downstream consequences for hypertension and cardiovascular-renal remodeling, differ substantially depending on the level and the location of the RGS2 system being probed. A brake present in immune cells appears dispensable for pressor responses in mice, whereas abundant RGS2 in vascular cells of patients with inherited angiotensin signaling antagonism exerts profound hypotensive and antiremodeling effects. Context, cellular identity, and tissue distribution are everything. The findings caution against assuming that a regulatory protein implicated in immune-driven inflammation will necessarily shape blood pressure outcomes when manipulated within the immune compartment.

The commentary authors look forward to future work from the Nakagawa group addressing the major limitations acknowledged in the study, including the angiotensin II doses and time points employed and the need for more selective targeting methods for myeloid-specific ablation. Such refinements could reveal subtler roles for myeloid RGS2 that the current model missed, or they could further cement the conclusion that the vascular and renal epithelium are where RGS2 truly determines the course of hypertensive disease. Either way, the convergence of a clean genetic experiment in mice with mechanistic insights from rare human syndromes offers a unusually clear picture of how one small regulatory protein helps set the tone of the renin-angiotensin system, and why understanding where a molecule acts matters as much as knowing what it does.

Subject of Research: The role of RGS2 regulation of angiotensin II signaling in hypertension and cardiovascular-renal remodeling

Article Title: Although myeloid‐cell RGS2 knockout does not affect Ang II–induced hypertension/organ damage in mice, high RGS2 in Gitelman/Bartter syndromes—human models of endogenous Ang II signaling antagonism—is associated with hypotensive/antiremodeling effects

Article References: Calò, L. A., Cacciapuoti, M., & Davis, P. A. (2026). Although myeloid‐cell RGS2 knockout does not affect Ang II –induced hypertension/organ damage in mice, high RGS2 in Gitelman/Bartter syndromes—human models of endogenous Ang II signaling antagonism—is associated with hypotensive/antiremodeling effects. Physiological Reports, 14(18), Article e71110. https://doi.org/10.14814/phy2.71110

Image Credits: AI Generated

DOI: 10.14814/phy2.71110

Keywords: RGS2, angiotensin II, hypertension, myeloid cells, Gitelman syndrome, Bartter syndrome, AT1 receptor, blood pressure, vascular remodeling, G-protein signaling, Although, myeloid

The renin-angiotensin-aldosterone system, or RAAS, is a peptidergic cascade with angiotensin II as its key effector. In healthy physiology it regulates blood pressure and fluid balance. In heart failure, reduced cardiac output, arterial underfilling and direct renal sympathetic stimulation push the system into overdrive, and the consequences are destructive: vasoconstriction, oxidative stress, inflammation, fibrosis of the heart and vasculature, and amplification of sympathetic nervous activity. Blocking this cascade with ACE inhibitors, angiotensin receptor blockers, angiotensin receptor-neprilysin inhibitors and mineralocorticoid receptor antagonists is a cornerstone of modern heart failure therapy. Yet guidelines do not routinely recommend these drugs after heart transplantation, and the question of whether the hormonal storm actually resolves once hemodynamics are corrected has remained largely unanswered.

To find out, the Vienna team enrolled patients with end-stage heart failure who were undergoing either heart transplantation or implantation of a left ventricular assist device, or LVAD, into a prospective registry. In total, 49 transplant recipients and 12 LVAD recipients were followed, with blood sampling shortly before and approximately six months after the intervention. The investigators measured NT-proBNP, the widely used marker of cardiac stress, plasma active renin concentration, aldosterone, and crucially the complete profile of circulating angiotensin peptides. Blood was drawn into tubes containing an inhibitor cocktail that instantly freezes angiotensin metabolism, allowing the researchers to capture a faithful snapshot, or fingerprint, of the circulating RAS at the moment of sampling.

The fingerprinting technique itself is a technical tour de force. Plasma samples were spiked with stable isotope-labeled internal standards for ten different angiotensin metabolites, then analyzed by liquid chromatography tandem mass spectrometry after solid-phase extraction. Because renin-dependent generation of angiotensin I is the rate-limiting step of the cascade, and ACE converts angiotensin I into angiotensin II, the relative abundance of downstream peptides such as angiotensin 1-7, angiotensin 1-5, angiotensin III and angiotensin IV reveals both the magnitude of systemic RAS activation and the mode of any pharmacological blockade. The sum of angiotensin I and angiotensin II served as a measure of the angiotensin burden carried by the classical RAS axis.

The results were unambiguous. After heart transplantation, the use of RAS inhibitors dropped significantly, as beta-blocker use fell from 63 to 2 percent and mineralocorticoid antagonist use collapsed from 55 to 8 percent, reflecting the standard de-escalation of heart failure drugs after transplant. In LVAD patients, by contrast, neurohormonal therapy remained broadly comparable before and after implantation, consistent with the strategy of continuing medication to promote reverse remodeling and myocardial recovery. Both interventions produced marked improvements in the visible signs of neurohumoral dysregulation. NT-proBNP fell from a median of 3015 to 1140 pg/mL after transplantation and from 8980 to 1836 pg/mL after LVAD implantation, while active renin concentration declined from 278 to 87 µIU/mL and from 847 to 131 µIU/mL respectively.

But the improvement stopped well short of normal. Not a single patient achieved normal NT-proBNP values after either intervention, and only 24 percent of transplant recipients and 33 percent of LVAD recipients reached normal renin levels. Plasma renin remained elevated in 76 percent of heart transplant patients and 67 percent of LVAD recipients, and in those patients clearly measurable angiotensin II persisted in the circulation. The angiotensin burden of the classical axis fell substantially after transplantation, from a median of 159 to 47 ng/L, and dropped numerically in the LVAD group from 214 to 42 ng/L, but it did not vanish. Aldosterone concentrations, notably, showed no significant change after either procedure. A tight correlation between renin and the combined angiotensin I plus angiotensin II levels, with a Spearman coefficient of 0.87, confirmed that renin remains the rate-limiting driver of the circulating cascade even after hemodynamic rescue.

Why does the hormonal system refuse to reset? The authors suggest a combination of mechanisms. In transplant recipients, persistent natriuretic peptide elevation has been attributed to cardiac denervation, immunosuppressive therapy, ventriculo-vascular uncoupling, endothelial dysfunction and subclinical allograft rejection. Prior studies have shown that natriuretic peptide levels peak within months of transplantation and decline gradually, but rarely normalize even years later; importantly, a late rise in NT-proBNP correlates strongly with allograft rejection, making these biomarkers clinically meaningful rather than mere curiosities. In LVAD patients, the picture is complicated by the devices themselves. Continuous-flow pumps may fail to stimulate arterial baroreceptors the way pulsatile flow does, potentially desensitizing receptors and raising intrinsic sympathetic tone, which in turn drives RAAS activation. Non-pulsatile kidney perfusion may independently activate the system, and preclinical work has linked continuous flow to impaired endothelial function, renal cortical artery hypertrophy and inflammatory infiltration.

The clinical implications are considerable. Ongoing angiotensin II spill-over is not a benign biochemical footnote: the peptide promotes the very processes, remodeling, fibrosis, inflammation and vascular dysfunction, that produce complications such as right ventricular failure in LVAD patients and possibly graft injury in transplant recipients. The study’s findings support a rationale for cardioprotective treatment, particularly with RAS inhibitors, in most patients after both transplantation and LVAD implantation, even though current transplant guidelines do not routinely recommend these agents. The Vienna group cautions, however, that this remains a hypothesis in this population. The impact of RAS inhibition specifically after transplantation and mechanical support should be tested in dedicated studies, and the long-term consequences of such a strategy, including interactions with immunosuppression and renal function, need careful evaluation.

Beyond its immediate therapeutic message, the study offers a conceptual shift. It reframes advanced heart failure not simply as a pumping problem that surgery can fix, but as a systemic neurohormonal disease whose imprint survives the replacement of the organ that caused it. The angiotensin fingerprints captured by mass spectrometry provide a new window into individual RAS regulation, showing exactly how pharmacological blockade reshapes the peptide landscape and where activation persists. For the growing population of patients living with transplanted hearts or mechanical circulatory support, the message is that the endocrine apparatus retains a memory of the failure it once served, and that memory may be a modifiable target for improving long-term outcomes.

Subject of Research: Persistent renin-angiotensin system activation and neurohormonal memory after heart transplantation or LVAD implantation in end-stage heart failure patients

Article Title: Memory of the renin-angiotensin system following heart transplantation or implantation of a left ventricular assist device

Article References: Memory of the renin-angiotensin system following heart transplantation or implantation of a left ventricular assist device. (n.d.). https://doi.org/10.1007/s00392-026-03018-x

Image Credits: AI Generated

DOI: 10.1007/s00392-026-03018-x

Keywords: heart failure, heart transplantation, LVAD, renin-angiotensin system, angiotensin II, NT-proBNP, neurohormonal activation, mass spectrometry, cardiac remodeling, RAS inhibitors, aldosterone, plasma renin

Insulin resistance is a central feature of metabolic syndrome and a powerful driver of type 2 diabetes and cardiovascular disease. In the modern antiretroviral therapy era, people living with HIV increasingly face a heightened burden of metabolic disorders, often at younger ages than the general population. While the shift to integrase strand transfer inhibitor-based regimens has dramatically improved viral suppression and drug tolerability, these regimens have also been linked to disproportionate weight gain and metabolic dysfunction, particularly among women. Understanding how sex, HIV, and related biological pathways interact to influence insulin resistance is therefore a pressing question for populations shouldering a dual burden of infectious and non-communicable diseases.

The research team recruited participants from the medical outpatient clinic between August 2023 and April 2024. People living with HIV had to have been on antiretroviral therapy for at least six months and achieved viral suppression, defined as a viral load below 50 copies per milliliter. Participants with conditions that could distort metabolic or inflammatory measurements, such as pregnancy, active malignancy, acute infections, or severe renal or hepatic disease, were excluded. After an overnight fast of eight to twelve hours, blood samples were collected and processed within two hours, with plasma and serum aliquots stored at minus 80 degrees Celsius until analysis.

In the laboratory, fasting glucose and lipid profiles were measured with automated clinical chemistry analyzers, while fasting insulin was quantified by immunoassay. HOMA-IR was calculated from fasting insulin and glucose values, with participants classified as insulin resistant at a threshold of 1.9 or above. The team also measured high-sensitivity C-reactive protein and interleukin-17A, a pro-inflammatory cytokine linked to Th17 immune responses, as well as angiotensin II, the primary effector peptide of the renin-angiotensin system, which has been implicated in promoting insulin resistance by interfering with insulin signaling and inducing oxidative stress in skeletal muscle and adipose tissue. All enzyme-linked immunosorbent assays were performed in duplicate with intra-assay coefficients of variation below 8 percent.

The cohort comprised 79 men and 154 women, with comparable median ages of roughly 48 years. Women carried a less favorable adiposity profile, with a higher mean body mass index of 26.9 versus 23.5 kilograms per square meter and larger waist circumferences of 88.3 versus 83.2 centimeters, indicating greater central obesity. Women also showed higher fasting insulin levels and higher HOMA-IR scores, together with a higher prevalence of insulin resistance at 17.5 percent compared with 12.7 percent in men. Inflammatory markers trended higher among women, although the variability was substantial, while men exhibited markedly higher alanine aminotransferase levels, hinting at sex-specific hepatic or metabolic stress.

The adjusted regression analysis for the overall population delivered two striking results. Female sex was independently associated with higher HOMA-IR, with a beta coefficient of 0.95 and a p-value of 0.037, while HIV-positive status was independently associated with lower HOMA-IR, with a beta of minus 1.54 and a p-value of 0.046. Hypertension, triglycerides, estimated glomerular filtration rate, angiotensin II, and interleukin-17A were not independently associated with insulin resistance in the combined model. The inverse HIV association was particularly pronounced among women, where HIV-positive status remained significantly linked to lower HOMA-IR after adjustment, with a beta of minus 2.31 and a p-value of 0.049.

Sex-stratified analyses revealed further divergence. Among men, hypertension was independently associated with higher HOMA-IR, with a beta of 0.61 and a p-value of 0.019, while higher estimated glomerular filtration rate was linked to lower insulin resistance, with a beta of minus 0.01 and a p-value of 0.029. This supports the well-established bidirectional relationship between hypertension and insulin resistance, in which insulin resistance promotes endothelial dysfunction, sympathetic nervous system activity, and oxidative stress, all of which can elevate blood pressure. The kidney finding suggests that impaired renal function, increasingly recognized as both a consequence and a contributor to insulin resistance through chronic inflammation, oxidative stress, and altered insulin clearance, may be an important metabolic correlate in men but not in women.

The authors caution that several findings warrant careful interpretation. Neither angiotensin II nor interleukin-17A was independently associated with HOMA-IR, a result that contrasts with experimental evidence implicating renin-angiotensin system activation and inflammatory pathways in insulin resistance. The researchers note that circulating biomarker concentrations may not fully capture tissue-level activity, and the cross-sectional design precludes any inference about temporal relationships. They also emphasize that the apparent sex differences were not formally tested for interaction, so statistical significance in one sex but not the other does not confirm true effect modification. The relatively small male subgroup of 79 participants may have reduced statistical power and produced less stable regression estimates.

The relatively low mean HOMA-IR values observed in this Zambian cohort also merit attention. Similar findings have been reported in other sub-Saharan African populations and may reflect differences in body composition, dietary patterns, physical activity, and genetic background compared with Western populations, where HOMA-IR thresholds of 2.5 to 3.0 are commonly applied. The authors suggest that thresholds derived from European and North American populations may not be directly applicable to African populations, underscoring the need for population-specific reference values in metabolic risk assessment.

Despite these limitations, the study offers a valuable exploratory framework for understanding sex-specific metabolic risk in African populations affected by HIV. The absence of data on physical activity, dietary intake, and menopausal status, particularly important given the median female age of 48 years, leaves open the question of whether the observed patterns reflect biological sex differences, lifestyle factors, hormonal status, or their interactions. The authors call for larger, adequately powered studies integrating comprehensive lifestyle, hormonal, inflammatory, and treatment-related assessments. In the meantime, the findings argue for incorporating sex-specific considerations into the assessment and management of insulin resistance, particularly in populations living with HIV, where metabolic risk pathways may diverge sharply between men and women.

Subject of Research: Sex differences in insulin resistance and associated metabolic and inflammatory markers among adults with and without HIV in Zambia

Article Title: Sex differences in insulin resistance and associated metabolic and inflammatory markers among adults with and without HIV in Zambia

Article References: Sibbenga, F., Chisompola, D., Chipuma, M., Chakulya, M., Lwiindi, P., Liamba, M. A., Hamooya, B. M., Povia, J. P., Liweleya, S., & Masenga, S. K. (2026). Sex differences in insulin resistance and associated metabolic and inflammatory markers among adults with and without HIV in Zambia. Physiological Reports, 14(17), Article e71093. https://doi.org/10.14814/phy2.71093

Image Credits: AI Generated

DOI: 10.14814/phy2.71093

Keywords: insulin resistance, HOMA-IR, HIV, Zambia, sex differences, hypertension, kidney function, angiotensin II, interleukin-17A, antiretroviral therapy, metabolic syndrome, inflammation